DESCRIPTION (Applicant's Description): Michael S. Kapiloff, M.D., Ph.D., is applying for a Clinical Investigator Award (K08) for support of a three-year postdoctoral fellowship in human genetics which he shall be performing in the laboratory of Dr. Raymond White in the Huntsman Cancer Institute at the University of Utah. In June, 1995, Dr. Kapiloff shall finish his residency in General Pediatrics at the University of Utah Affiliated Hospitals in Salt Lake City. In 1992, he completed the Medical Scientist Training Program at the University of California, San Diego, where he finished his doctoral dissertation in molecular biology in the laboratory of Dr. Michael G. Rosenfeld. Entering Dr. White's lab will mark a return to basic science and neuromolecular biology. There Dr. Kapiloff shall be continuing research in progress on neurofibromatosis, an inherited illness with a predisposition to cancer. Neurofibromatosis type I is caused by mutations in the tumor-suppressor gene NF1, which encodes the gene product neurofibromin. Neurofibromin contains a "ras-GTPase Activating Protein" domain (GRD) which is capable of complementing the IRA1 and IRA2 mutations in yeast and is capable of reversing transformation in some transformed cell lines. Neurofibromin is, however, a very large protein with over two thousand amino acid residues of unknown function. In this application Dr. Kapiloff proposes experiments to determine the domain structure and non-GAP functions of neurofibromin. These experiments will take advantage of NF1 mutations that lie outside of the GRD that have been described in patients with neurofibromatosis. These mutations will be introduced into full-length and truncated NF1 cDNAs, expressed and assayed for biochemical (GTPase of p20ras-binding) activity, ability to correctly target intracellular neurofibromin, or ability to complement wild-type functions in cells. The laboratory of Dr. Raymond L. White has contributed significantly to the cloning of neurofibromin, the discovery of native NF1 mutations and the elucidation of neurofibromin's interaction with ras. Why neurofibromin is such a large molecule and why it is so critical to proper growth control may not be fully explained by its GAP activity. The appropriate cell lines, molecular reagents, and expertise concerning carcinogenesis and human genetics available here make Dr. White's laboratory an ideal setting for Dr. Kapiloff's proposed experiments. Neighboring laboratories include those of Dr. Richard Cawthon and Dr. David Viskochil, who are also heavily invested in neurofibromatosis research. In this environment Dr. Kapiloff hopes to extend their knowledge of tumor suppressors and their interactions with mitogenic pathways.